Although targeted therapies have been developed to treat cancers with well-elucidated molecular pathways, these therapies still remain ineffective as innate or acquired resistance often limits their ability to produce initial or durable responses. Patients with colorectal cancer (CRC) that harbor a BRAF mutation have the poorest outcomes of all CRC patients and are resistant to EGFR and BRAF directed therapies as single agents, such as cetuximab and vemurafenib. Ligands have significant responsibility for fueling oncogenic pathways, yet there are few ligand-targeted therapies in clinical development. We developed a novel multi-targeting ligand trap, LC015, directed against ligands to the ERBB/HER family of receptor tyrosine kinases (RTKs). LC015 binds to a wide spectrum of ERBB ligands including TGFa, betacellulin (BTC) and heregulin 1 (HRG1/NRG1), and prevents ligand binding to multiple ERBB receptors including EGFR, ERBB3/HER3 and ERBB4/HER4. Given its unique ability to capture a wide spectrum of ligands, LC015 may exhibit an improved activity over agents that only target EGFR, such as cetuximab, because it may prevent MAP Kinase (MAPK) signaling by EGFR/ERBB2 heterodimers and PI3K-AKT signaling by ERBB2/ERBB3 heterodimers. In fact, HRG upregulation and high levels of phospho-AKT have been correlated with resistance to cetuximab. Furthermore, in BRAF mutant CRC cells treated with vemurafenib, the MAPK/AKT pathway is still active despite mutant BRAF inhibition, because of ligand dependent feedback activation of EGFR. Based on these findings, our hypothesis is that a combination of LC015 with vemurafenib should be able to overcome EGFR/ERBB driven MAPK and PI3K-AKT activation. In this proposal, we plan to demonstrate that LC015 in combination with vemurafenib prevents feedback activation of EGFR that occurs in BRAF mutant CRC cells treated with vemurafenib, and that the combination results in greater tumor growth inhibition in BRAF mutant CRC xenografts than a combination of cetuximab with vemurafenib. This work has the potential to advance treatment options for CRC patients with BRAF mutations, who derive little benefit from current treatment regimens, especially compared with other molecular subgroups of CRC. This proposal introduces a novel, ligand directed therapeutic that can be explored as a single agent or in rational combination with other targeted therapies or chemotherapies. This work should also help to validate the multi-targeting, ligand capture platform for additional ligand targets, replete with development and commercialization opportunities.